Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

within the ITCC Biology and Preclinical Evaluation Committee

Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

within the ITCC Biology and Preclinical Evaluation Committee

Science

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.

MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.

RESULTS: Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.

CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.

Original language	English
Pages (from-to)	599-609
Number of pages	11
Journal	Anticancer Research
Volume	36
Issue number	2
Publication status	Published - Feb 2016

Bibliographical note

Keywords

Animals
Antineoplastic Combined Chemotherapy Protocols/pharmacology
Apoptosis/drug effects
Blotting, Western
Bone Neoplasms/drug therapy
Cell Cycle/drug effects
Cell Cycle Proteins/antagonists & inhibitors
Cell Proliferation/drug effects
Child
Drug Synergism
Female
Flow Cytometry
Humans
Medulloblastoma/drug therapy
Mice
Mice, Nude
Neoplasms/drug therapy
Neuroblastoma/drug therapy
Protein-Serine-Threonine Kinases/antagonists & inhibitors
Proto-Oncogene Proteins/antagonists & inhibitors
Pteridines/administration & dosage
Rhabdomyosarcoma/drug therapy
Sarcoma, Ewing/drug therapy
Tumor Cells, Cultured
Vincristine/administration & dosage
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@article{6a55c967beb9412ca0170d2afc56c11a,

title = "Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies",

abstract = "BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.RESULTS: Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.",

keywords = "Animals, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, Blotting, Western, Bone Neoplasms/drug therapy, Cell Cycle/drug effects, Cell Cycle Proteins/antagonists & inhibitors, Cell Proliferation/drug effects, Child, Drug Synergism, Female, Flow Cytometry, Humans, Medulloblastoma/drug therapy, Mice, Mice, Nude, Neoplasms/drug therapy, Neuroblastoma/drug therapy, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Proto-Oncogene Proteins/antagonists & inhibitors, Pteridines/administration & dosage, Rhabdomyosarcoma/drug therapy, Sarcoma, Ewing/drug therapy, Tumor Cells, Cultured, Vincristine/administration & dosage, Xenograft Model Antitumor Assays",

author = "{within the ITCC Biology and Preclinical Evaluation Committee} and Samuel Abbou and Claudia Lanvers-Kaminsky and Estelle Daudigeos-Dubus and {LE Dret}, Ludivine and Corinne Laplace-Builhe and Jan Molenaar and Gilles Vassal and Birgit Geoerger",

year = "2016",

month = feb,

language = "English",

volume = "36",

pages = "599--609",

journal = "Anticancer Research",

issn = "0250-7005",

publisher = "International Institute of Anticancer Research",

number = "2",

}

TY - JOUR

T1 - Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

AU - within the ITCC Biology and Preclinical Evaluation Committee

AU - Abbou, Samuel

AU - Lanvers-Kaminsky, Claudia

AU - Daudigeos-Dubus, Estelle

AU - LE Dret, Ludivine

AU - Laplace-Builhe, Corinne

AU - Molenaar, Jan

AU - Vassal, Gilles

AU - Geoerger, Birgit

PY - 2016/2

Y1 - 2016/2

N2 - BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.RESULTS: Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.

AB - BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.RESULTS: Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.

KW - Animals

KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology

KW - Apoptosis/drug effects

KW - Blotting, Western

KW - Bone Neoplasms/drug therapy

KW - Cell Cycle/drug effects

KW - Cell Cycle Proteins/antagonists & inhibitors

KW - Cell Proliferation/drug effects

KW - Child

KW - Drug Synergism

KW - Female

KW - Flow Cytometry

KW - Humans

KW - Medulloblastoma/drug therapy

KW - Mice

KW - Mice, Nude

KW - Neoplasms/drug therapy

KW - Neuroblastoma/drug therapy

KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors

KW - Proto-Oncogene Proteins/antagonists & inhibitors

KW - Pteridines/administration & dosage

KW - Rhabdomyosarcoma/drug therapy

KW - Sarcoma, Ewing/drug therapy

KW - Tumor Cells, Cultured

KW - Vincristine/administration & dosage

KW - Xenograft Model Antitumor Assays

M3 - Article

C2 - 26851014

SN - 0250-7005

VL - 36

SP - 599

EP - 609

JO - Anticancer Research

JF - Anticancer Research

IS - 2

ER -

Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

Abstract

Bibliographical note

Keywords

UN SDGs

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Cite this